This invention relates to IP receptor antagonists, especially to certain 2-(substituted-phenyl)amino-imidazoline derivatives; pharmaceutical compositions containing them; and methods for their use as therapeutic agents.
Prostaglandins or prostanoids (PG) are a group of biologically active compounds derived from membrane phospholids and are formed from certain polyunsaturated fatty acids. They fall into several main classes designated by letters including D, E, F, G, H, and I (prostacyclin). The main classes are further subdivided as indicated by subscripts 1, 2, or 3, which reflect the fatty acid precursor, for example PGE1 or PGE2. Prostanoids are ubiquitously produced and the rate of their production usually increases in response to diverse stimuli. They thereby exhibit a wide variety of pharmacological properties.
The diversity of effects of prostanoids can be explained by the existence of a number of distinct receptors that mediate their action. The receptors have been named for the natural prostaglandin for which they have the greatest affinity and have been divided into five main types, designated as DP (PGD2), FP (PG2xcex1), IP (PGI2), TP (TXA2), AND EP (PGE2). Additional information relating to prostaglandins and their receptors are described in Goodman and Gillman""s, The Pharmacological Basis of Therapeutics, ninth edition, McGraw-Hill, New York, 1996, Chapter 26, pages 601-616.
Prostanoids are generated by most cells in response to mechanical, thermal or chemical injury and inflammatory insult, and are responsible for the sensitization or direct activation of nearby sensory nerve endings. The hyperalgesic effects (an increased responsiveness to a stimulus that is normally painful) of several prostanoids have been reported in several inflammatory models of nociception. Even though PGE2 has attained wide recognition as the primary mediator of hyperalgesia, significant quantities of other prostanoids, including PGI2, are released by injury or inflammation. Indeed, when the effects of PGE2 and PGI2 on sensory neurons are compared directly, PGI2 is equally or more effective as a hyperalgesic or sensitizing agent both in vivo and in vitro assays. However, to date, there have been no selective receptor antagonists which could unequivocally characterize the prostanoid receptor subtype(s) that mediate the sensitizing effects of PGE2 or PGI2.
When the intrinsic instability and pharmacokinetic properties of PGI2 are taken into account, a preponderance of in vivo analgesia studies in rodents suggest that PGI2 plays a major role in the induction of hyperalgesia. Likewise, in vitro studies provide substantial evidence to suggest that IP receptors act as important modulators of sensory neuron function. Since IP receptors in sensory neurons are coupled to activation of both adenylyl cyclase and phospholipase C, and hence, cAMP-dependent protein kinase and protein kinase C, these receptors can exert powerful effects on ion channel activity and thus neurotransmitter release.
Recent compelling evidence for a prominent role for IP (PGI2-preferring) receptors in inflammatory pain has been obtained from recent studies in transgenic mice lacking the IP receptor (T. Murata et al., Nature 1997, 388, 678-682). In these animals, the acetic acid-induced writhing response or the carrageenan-induced paw edema was reduced to levels similar to those seen with administration of indomethacin in wild-type mice. In contrast, spinal nociceptive reflexes measured by the tail-flick and hot-plate test were normal. The modest writhing response induced by PGE2 was unchanged in the transgenic animals.
Based upon these observations, the compounds of the present invention are expected to be effective anti-nociceptive agents.
In addition to being mediators of hyperalgesia, prostanoids are known to be generated locally in the bladder in response to physiologic stimuli such as stretch of the detrusor smooth muscle, injuries of the vesical mucosa, and nerve stimulation (K. Anderson, Pharmacological Reviews 1993, 45(3), 253-308). PGI2 is the major prostanoid released from the human bladder. Several lines of evidence suggest that prostanoids may be the link between detrusor muscle stretch produced by bladder filling and activation of C-fiber afferents by bladder distension. It has been proposed that prostanoids may be involved in the pathophysiology of bladder disorders, e.g., bladder outlet obstruction, and conditions associated with urinary incontinence such as urge incontinence, stress incontinence, and bladder hyperreactivity. Therefore, antagonists of prostanoid IP receptors are expected to be useful in the treatment of such conditions.
Certain 2-(substituted-phenyl)amino-imidazoline compounds have been exemplifed in the patent literature. For example, European Patent No. 0 017 484 B1 (Fujisawa Pharmaceutical) discloses compounds useful for treatment of hypertensive, inflammatory and gastrointestinal disorder and relief from pain of various origins; U.S. Pat. No. 4,287,201 (Olson et al.) discloses compounds useful in delaying the onset of egg production in young pullets, interrupting egg production in mature hens, and in producing an artificial molt; U.S. Pat. No. 4,396,617 (Dolman and Kuipers) discloses fungicides active against rust of beans, brown rust of wheat and mildew on cereals; U.S. Pat. No. 4,889,868 (Huang) discloses lipoxygenase and phospholipase C inhibitors and platelet-activating factor receptor antagonists useful for the treatment of inflammatory or allergic conditions and myocardial infarctions; U.S. Pat. No. 5,326,776 (Winn et al.) discloses compounds that are angiotensin II receptor antagonists; British Patent Application No. GB 2 038 305 (Duphar International Research) discloses compounds that can be used to inhibit growth of side shoots tobacco or tomato plants, or inhibit lawn growth, or dwarf ornamental plants; and PCT Published Application No. WO 96/30350 (Fujisawa Pharmaceutical) discloses compounds useful as a medicament for prophylactic and therapeutic treatment of nitric oxide synthase-mediated diseases.
The disclosures of these and other documents referred to throughout this application are incorporated herein by reference.
This invention provides compounds represented by Formula I: 
wherein:
R1 is a group represented by formula (A), (B) or (C); 
wherein:
X is independently in each occurrence S, O or N;
R2 and R4 are each independently in each occurrence:
(1) hydrogen,
(2) alkyloxy, or
(3) halogen;
R3 is independently in each occurrence:
(1) alkyl,
(2) cycloalkyl,
(3) halogen,
(4) heterocyclyl,
(5) xe2x80x94NR8R9,
(6) xe2x80x94(CH2)mCONR8R9, wherein m is an integer from 0 to 3,
(7) xe2x80x94(CH2)mSO2NR8R9, wherein m is an integer from 0 to 3,
(8) xe2x80x94(CH2)mNR7COR9, wherein m is an integer from 0 to 3,
(9) xe2x80x94(CH2)mNR7SO2R9, wherein m is an integer from 0 to 3,
(10) xe2x80x94(CH2)mNR7C(V)NR8R9, wherein V is S or O, and m is an integer from 0 to 3,
(11) xe2x80x94(CH2)mOY wherein m is an integer from 0 to 3, and Y is: hydrogen, alkyl, alkyloxyalkyl, cycloalkyl, haloalkyl, hydroxyalkyl, heterocyclyl, or carboxyalkyl, or
(12) xe2x80x94O(CH2)nZ wherein n is an integer from 1 to 4 and Z is: cycloalkyl, hydroxyalkyl, cycloalkyloxy, heterocyclyl, aryloxy, heteroaryl, xe2x80x94COR9, xe2x80x94CONR8R9, xe2x80x94SO2R9, xe2x80x94SO2NR8R9, xe2x80x94NR7SO2R9, or unsubstituted aryl or mono-, di-, or tri-substituted aryl, the substituents being independently selected from alkyl, halogen, or alkyloxy;
R5 is independently in each occurrence:
(1) xe2x80x94(CH2)mOY wherein m is an integer from 0 to 3, and Y is: hydrogen, alkyl, alkyloxyalkyl, cycloalkyl, haloalkyl, hydroxyalkyl, heterocyclyl, or carboxyalkyl, or
(2) xe2x80x94O(CH2)nZ wherein n is an integer from 1 to 4, and Z is: cycloalkyl, hydroxyalkyl, cycloalkyloxy, heterocyclyl, aryloxy, heteroaryl, xe2x80x94COR9, xe2x80x94CONR8R9, xe2x80x94SO2R9, xe2x80x94SO2NR8R9, or xe2x80x94NR7SO2R9, or unsubstituted aryl or mono-, di-, or tri-substituted aryl, the substituents being independently selected from alkyl, halogen, or alkyloxy;
R6 is independently in each occurrence:
(1) hydrogen,
(2) xe2x80x94COR9,
(3) xe2x80x94CONR8R9,
(4) xe2x80x94C(V)NR8R9 wherein V is O or S,
(5) xe2x80x94SO2R9, or
(6) xe2x80x94SO2NR8R9;
R7 and R8 are each independently in each occurrence:
(1) hydrogen,
(2) alkyl, or
(3) hydroxyalkyl;
R9 is independently in each occurrence:
(1) alkyl,
(2) cycloalkyl,
(3) arylalkyl,
(4) hydroxyalkyl,
(5) haloalkyl,
(6) heterocyclyl,
(7) unsubstituted aryl or mono-, di-, or tri-substituted aryl, the substituents being independently selected from alkyl, halogen, or alkyloxy, or
(8) heteroaryl;
or R8 and R9 are taken together with the nitrogen to which they are attached to form a 5- or 6-membered monocyclic saturated or unsaturated ring, and in which the ring is optionally substituted or unsubstituted with oxo;
or R7 and R9 are taken together with the nitrogen to which they are attached to form a 5- or 6-membered monocyclic saturated or unsaturated ring, and in which the ring is optionally substituted or unsubstituted with oxo;
or a pharmaceutically acceptable salt or a crystal form thereof.
This invention further provides pharmaceutical compositions containing as an ingredient a therapeutically effective amount of a compound of Formula I or its pharmaceutically acceptable salt or a crystal form thereof, in admixture with one or more suitable carriers.
This invention further provides a method for treating pain conditions from a wide variety of causes, including but not limited to, inflammatory pain, surgical pain, visceral pain, dental pain, premenstrual pain, central pain, pain due to bums, migraine or cluster headaches, nerve injury, neuritis, neuralgias, poisoning, ischemic injury, interstitial cystitis, cancer pain, viral, parasitic or bacterial infection, and post-traumatic injuries (including fractures and sports injuries); inflammation from a variety of causes, including but not limited to, bacterial, fungal or viral infections, rheumatoid arthritis, osteoarthritis, surgery, bladder infection or idiopathic bladder inflammation, over-use, old age, nutritional deficiencies, prostatis, conjunctivitis, pain associated with functional bowel disorders such as Irritable bowel syndrome; and additionally for treating bladder disorders associated with bladder outlet obstruction, and urinary incontinence (including urge incontinence, stress incontinence, and bladder hyperreactivity); asthma; and septic shock in mammals comprising administering to a mammal in need of a therapeutically effective amount of a compound of Formula I or its pharmaceutically acceptable salt or a crystal form thereof.